title: Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): structure-activity relationships and strategies for the elimination of reactive metabolite formation.
abstract: The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay.
authors.affiliation: Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. daniel.p.walker@pfizer.com
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Walker
authors.forename: F Christopher
authors.initials: FC
authors.lastname: Bi
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Bauman
authors.forename: Sabrina X
authors.initials: SX
authors.lastname: Zhao
authors.forename: John R
authors.initials: JR
authors.lastname: Soglia
authors.forename: Gary E
authors.initials: GE
authors.lastname: Aspnes
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Kung
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Klug-McLeod
authors.forename: Michael P
authors.initials: MP
authors.lastname: Zawistoski
authors.forename: Molly A
authors.initials: MA
authors.lastname: McGlynn
authors.forename: Robert
authors.initials: R
authors.lastname: Oliver
authors.forename: Matthew
authors.initials: M
authors.lastname: Dunn
authors.forename: Jian-Cheng
authors.initials: JC
authors.lastname: Li
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Richter
authors.forename: Beth A
authors.initials: BA
authors.lastname: Cooper
authors.forename: John C
authors.initials: JC
authors.lastname: Kath
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Hulford
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Autry
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Luzzio
authors.forename: Ethan J
authors.initials: EJ
authors.lastname: Ung
authors.forename: W Gregory
authors.initials: WG
authors.lastname: Roberts
authors.forename: Peter C
authors.initials: PC
authors.lastname: Bonnette
authors.forename: Leonard
authors.initials: L
authors.lastname: Buckbinder
authors.forename: Anil
authors.initials: A
authors.lastname: Mistry
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Griffor
authors.forename: Seungil
authors.initials: S
authors.lastname: Han
authors.forename: Angel
authors.initials: A
authors.lastname: Guzman-Perez
mesh_terms: D000818:Animals; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D015195:Drug Design; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D008968:Molecular Conformation; D015394:Molecular Structure; D010024:Osteoporosis / Q000188:drug therapy; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D011743:Pyrimidines; D051418:Focal Adhesion Kinase 2; D051416:Focal Adhesion Protein-Tyrosine Kinases